AATS Annual Meeting 2015 | Seattle, WA | April 27, 2015 Appropriate Patient Selection or Healthcare Rationing? Lessons from Surgical Aortic Valve Replacement in The PARTNER I Trial Wilson Y. Szeto, MD on behalf of The PARTNER Trial Investigators and The PARTNER Publications Office

Investigator, Steering committee member of the PARTNER trialInvestigator, Steering committee member of the PARTNER trial Edwards LifesciencesEdwards Lifesciences Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below. Affiliation/Financial Relationship Company Disclosure Statement of Financial Interest Wilson Y. Szeto, MD

Background Surgical aortic valve replacement (SAVR) is being challenged by transcatheter aortic valve replacement (TAVR) for patients considered at high surgical risk.Surgical aortic valve replacement (SAVR) is being challenged by transcatheter aortic valve replacement (TAVR) for patients considered at high surgical risk. There is increasing pressure on surgeons and institutions to improve quality metrics and outcomes while reducing cost of medical care.There is increasing pressure on surgeons and institutions to improve quality metrics and outcomes while reducing cost of medical care. Surgeons considering SAVR in high risk patients risk failing quality metrics.Surgeons considering SAVR in high risk patients risk failing quality metrics.

Objectives / Questions The Placement of Aortic Transcatheter Valves (PARTNER) trial provides insight into outcomes after surgical AVR in high-risk patients at extreme of traditional indications for SAVR. 1) Are surgical outcomes after high risk SAVR accurately predicted by current national benchmarks? 2) Is intermediate term survival after high risk AVR commensurate with that of the matched general population seen in previous studies? 3) Is there a subset of elderly patients whose risk of mortality after SAVR is exceptionally high (with survival worse than treatment without AVR, i.e. futility)?

Study Design Symptomatic Severe Aortic Stenosis ASSESSMENT: High-Risk AVR Candidate 3,105 Total Patients Screened ASSESSMENT: High-Risk AVR Candidate 3,105 Total Patients Screened Cohort B (Inoperable) n=358 Cohort B (Inoperable) n=358 Cohort A (High Surgical Risk) n=699 Cohort A (High Surgical Risk) n=699 Did not undergo SAVR (n=38) -Died before procedure: 5 -Deteriorated before procedure: 5 -Refused: 17 -Withdrew: 11 Did not undergo SAVR (n=38) -Died before procedure: 5 -Deteriorated before procedure: 5 -Refused: 17 -Withdrew: 11 Crossover from TAVR to Medical Therapy: 2 Allocated to SAVR n=351 Allocated to SAVR n=351 Allocated to Medical Therapy n=179 Allocated to Medical Therapy n=179 Received Medical Therapy n=181 Received Medical Therapy n=181 ReceivedSAVR n=351 ReceivedSAVR n=351 Allocated to TAVR (n=348) Allocated to TAVR (n=348) Allocated to TAVR (n=179) Allocated to TAVR (n=179)

Patient Population 699 patients with severe symptomatic AS were enrolled into PARTNER 1A from patients with severe symptomatic AS were enrolled into PARTNER 1A from Of the 351 patients randomized to SAVR, 313 underwent AVR (as treated cohort).Of the 351 patients randomized to SAVR, 313 underwent AVR (as treated cohort). –28 patients withdrew / refused therapy –10 patients deteriorated to an inoperable status 181 patients in PARTNER 1B (inoperable cohort) randomized to medical therapy were used as reference for survival without valve replacement.181 patients in PARTNER 1B (inoperable cohort) randomized to medical therapy were used as reference for survival without valve replacement.

Methodology Procedural outcome and primary safety endpoints were compared to national quality benchmarks for SAVR defined according to the STS Database Version 2.61.Procedural outcome and primary safety endpoints were compared to national quality benchmarks for SAVR defined according to the STS Database Version Intermediate term survival comparison with matched general population was performed using 2008 US life tables.Intermediate term survival comparison with matched general population was performed using 2008 US life tables. Incremental risk factors for mortality were identified from 102 possible risk factors.Incremental risk factors for mortality were identified from 102 possible risk factors.

Patient Characteristics (1) No. (%) or Mean ± SD Demographics Female 134 (43) Age (y) 84 ± 6.3 Body Mass Index (kg/m 2 ) 27 ± 5.7 Symptoms NYHA Class 3 or (95) Predicted operative mortality By benchmark available at time of enrollment (%) 12 ± 3.4 Cardiac Comorbidities Coronary Artery Disease 241 (77) Previous MI 90 (29) Atrial Fibrillation 69 (22)

Patient Characteristics (2) No. (%) or Mean ± SD Non-Cardiac Comorbidities Peripheral Arterial Disease 210 (67) CVD 108 (35) Diabetes 128 (41) Chronic Pulmonary Disease 147 (47) Renal Disease 69 (22) Hepatic Disease 9 (2.9) Previous Procedures PCI 101 (32) CABG 140 (45) Pacemaker 70 (22) Echocardiographic Characteristics AV peak velocity (cm/sec) 422 ± 70 AV area (cm 2 ) 0.64 ± 0.19 AV mean gradient (mmHg) 43 ± 14 Ejection fraction (%) 53 ± 12

Operative Details / Variables (1) No. (%) or Mean ± SD Incision Full sternotomy 243 (78) Partial sternotomy 51 (16) Thoracotomy 18 (5.8) Aortic valve prosthesis Valve size (mm) (12) (40) (35) (12) (0.97)

Operative Details / Variables (2) No. (%) or Mean ± SD Prosthesis type Edwards Lifesciences Edwards Lifesciences 273 (87) St. Jude St. Jude 3 (0.95) Carbomedics mechanical Carbomedics mechanical 4 (1.3) Medtronic Medtronic 12 (3.8) Sorin Sorin 7 (2.2) Unspecified porcine Unspecified porcine 1 (0.32) Unspecified Unspecified 13 (4.2) Concomitant procedure Unanticipated CABG 21 (6.7) Support Aortic clamp time (min) 74 ± 29 Cardiopulmonary bypass time (min) 105 ± 41

Outcome Referenced to Contemporary STS Benchmarks OutcomeObserved No. (%) Expected Observed/Expected (68% CL) p Operative mortality 33 (10) 29 (9.3) 1.14 (1.01 – 1.29) 0.40 Stroke 8 (2.6) 11 (3.5) 0.73 (0.55 – 0.94) 0.40 Renal Failure 18 (5.8) 38 (12) 0.48 (0.38 – 0.60) Deep sternal wound infection 2 (0.64) 1.03 (0.33) 1.94 (0.91 – 3.1) 0.30 Postoperative length of stay > 14 days 83 (26) 56 (18) 1.48 (1.36 – 1.62) < OutcomeObserved No. (%) Expected Observed/Expected (68% CL) p Operative mortality 33 (10) 29 (9.3) 1.14 (1.01 – 1.29) 0.40 Stroke 8 (2.6) 11 (3.5) 0.73 (0.55 – 0.94) 0.40 Renal Failure 18 (5.8) 38 (12) 0.48 (0.38 – 0.60) Deep sternal wound infection 2 (0.64) 1.03 (0.33) 1.94 (0.91 – 3.1) 0.30 Postoperative length of stay > 14 days 83 (26) 56 (18) 1.48 (1.36 – 1.62) <0.0001

% Years Worse Survival Compared to Age Matched Population SAVR

Incremental Risk Factors for Mortality after SAVR Risk Factor Coefficient ± SE p Hazard Ratio (68% CL) Reliability (%) a Early decreasing hazard Previous CABG (less risk) ± (0.42 – 0.76) 88 Lower albumin b 7.0 ± n/a51 Longer aortic clamp time c 0.95 ± n/a60 Intermediate-term hazard Smaller BMI d 0.99 ± n/a64 History of cancer 0.86 ± (1.7 – 3.2) 59 Severe prosthesis- patient mismatch 0.77 ± (1.6 – 2.8) 86 a.Percent of times variables appeared in 1000 bootstrap models b.(1/albumin), inverse transformation c.Log (aortic clamp time/75), logarithmic transformation d.(25/BMI) 2, inverse squared transformation

% Years Prior CABG Yes No Survival

1 Year Survival - Albumin Albumin (g/dL) Survival (%)

Aortic Clamp Time (min) Survival (%) 1 Year Survival - Aortic Clamp Time

1 Year Survival - BMI Body Mass Index Survival (%)

% Years Cancer No Yes Survival

% Years Mismatch None/Mild Severe Moderate Survival

% Years SAVR Medical Therapy Survival: SAVR vs Medical Therapy

% Years SAVR Medical Therapy Survival Age = 70 BMI = 36 Albumin = 2.9 Cancer

% Years Medical Therapy SAVR Survival Age = 90 BMI = 27 Albumin = 3.04 Cancer

% Years Medical Therapy SAVR Survival Age = 86 BMI = 21 Cancer Previous CABG

Conclusions (1) PARTNER 1A SAVR outcome was similar to contemporary benchmarks, suggesting these benchmarks may underestimate risk across high risk profiles.PARTNER 1A SAVR outcome was similar to contemporary benchmarks, suggesting these benchmarks may underestimate risk across high risk profiles. PARTNER 1A SAVR patients had worse survival compared to matched US population, suggesting a less selected population with higher morbidities and risk profile.PARTNER 1A SAVR patients had worse survival compared to matched US population, suggesting a less selected population with higher morbidities and risk profile.

Conclusions (2) PARTNER 1A SAVR patients have improved survival compared to PARTNER 1B patients randomized to medical therapy, although a few selected risk profiles demonstrated the futility of SAVR with worse outcome.PARTNER 1A SAVR patients have improved survival compared to PARTNER 1B patients randomized to medical therapy, although a few selected risk profiles demonstrated the futility of SAVR with worse outcome. PARTNER selection criteria for SAVR may be more appropriate and realistic, thus reflecting the contemporary surgical management of severe aortic stenosis in high risk patients.PARTNER selection criteria for SAVR may be more appropriate and realistic, thus reflecting the contemporary surgical management of severe aortic stenosis in high risk patients.

Thank you to the dedicated study teams at all the PARTNER Sites! Special thanks to the participants in this writing group Lars G. Svensson Jeevanantham Rajeswaran John Ehrlinger Rakesh M. Suri Craig R. Smith Michael Mack D. Craig Miller Patrick M. McCarthy Joseph E. Bavaria Lawrence H. Cohn Paul J. Corso Robert A. Guyton Vinod H. Thourani Bruce W. Lytle Mathew R. Williams John G. Webb Samir Kapadia E. Murat Tuzcu David J. Cohen Hartzell V. Schaff Martin B. Leon Eugene H. Blackstone